Product Selectivity Control in the Brønsted Acid-Mediated Reactions with 2-Alkynylanilines

Brønsted acid-catalysed/mediated reactions of the 2-alkynylanilines are reported. While metal-catalysed reactions of these valuable building blocks have led to the establishment of robust protocols for the selective, diverse-oriented syntheses of significant heterocyclic derivatives, we here demonstrate the practical advantages of an alternative methodology under metal-free conditions. Our investigation into the key factors influencing the product selectivity in Brønsted acid-catalysed/mediated reactions of 2-alkynylanilines reveals that different reaction pathways can be directed towards the formation of diverse valuable products by simply choosing appropriate reaction conditions. The origins of chemo- and regioselectivity switching have been explored through Density Functional Theory (DFT) calculations.


Introduction
The 2-alkynylanilines 1, readily available via Sonogashira cross-coupling of 2-haloanilines with terminal alkynes [1,2], are growing in importance as building blocks for constructing a wide variety of heterocyclic scaffolds [3][4][5].Significantly, these substrates enable access to challenging target skeletal diversity with good atom economy through product selectivity control.Indeed, controlling chemoselectivity also avoids the tedious separation of the desired reaction product from unwanted compounds, thereby further reducing waste and the cost of the process.Therefore, there is a growing demand for developing alternative strategies with high selectivity for producing pharmaceuticals and fine chemicals [6].In particular, the overcoming of the drawbacks of conventional methods [7] in the synthesis of pharmaceutical agents [8] from 2-alkynylanilines is relevant in academia and pharmaceutical industries due to their various biological activities including anticancer [9] and anti-neurodegenerative agents [10].Moreover, cascade synthetic approaches continue to be a focus of intensive research due to their unique features of reducing the time and labour of the synthetic process and their potential to rapidly increase molecular complexity in a single operation [11].Our ongoing interest in the synthesis of target heterocyclic scaffolds from aminoalkynes [12], encouraged us, supported by computational insights, to explore Brønsted acid-catalysed/mediated reactions of 2-alkynylaniline derivatives [13,14] as viable alternatives to the transition-metal catalysed methods (Scheme 1) [15][16][17][18][19].
The experimental results of this investigation, along with computational calculations aimed at rationalising the product selectivity control of these reactions, are set out below.The experimental results of this investigation, along with computational calculations aimed at rationalising the product selectivity control of these reactions, are set out below.

Discussion
Based on our investigations on divergent sequential reactions of the starting building blocks 1, we have previously identified the key factors able to direct their reaction with ketones towards the selective synthesis of 2,2,3-functionalised-2,3-dihydroquinolin-4 (1H)-ones 2, functionalised quinolines 3, or N-alkenyl indoles 4 (Scheme 2) [20].During this study, side-reactions leading to the 2-aminoarylketone 6a, derived by the hydration of the C-C triple bond of 1a, and to the highly dense quinoline 7a, derived by its regioselective dimerization, were also observed.Yet, two control experiments highlighted that p-TsOH•H2O promotes the formation of 6a and 7a in both EtOH at 80 °C and Toluene at 110 °C, but a different ratio between the two derivatives is observed.(Scheme 3).These findings suggested the possibility of directing the selectivity of the process through careful tuning of the reaction conditions.Consequently, we decided to explore the reactivity of the 2-phenylethynyl aniline 1a using Brønsted acids as promoters under a variety of reaction conditions.Scheme 1. Brønsted acid-catalysed/mediated reaction of 2-alkynylanilines 1.

Discussion
Based on our investigations on divergent sequential reactions of the starting building blocks 1, we have previously identified the key factors able to direct their reaction with ketones towards the selective synthesis of 2,2,3-functionalised-2,3-dihydroquinolin-4 (1H)ones 2, functionalised quinolines 3, or N-alkenyl indoles 4 (Scheme 2) [20].The experimental results of this investigation, along with computational calculations aimed at rationalising the product selectivity control of these reactions, are set out below.

Discussion
Based on our investigations on divergent sequential reactions of the starting building blocks 1, we have previously identified the key factors able to direct their reaction with ketones towards the selective synthesis of 2,2,3-functionalised-2,3-dihydroquinolin-4 (1H)-ones 2, functionalised quinolines 3, or N-alkenyl indoles 4 (Scheme 2) [20].During this study, side-reactions leading to the 2-aminoarylketone 6a, derived by the hydration of the C-C triple bond of 1a, and to the highly dense quinoline 7a, derived by its regioselective dimerization, were also observed.Yet, two control experiments highlighted that p-TsOH•H2O promotes the formation of 6a and 7a in both EtOH at 80 °C and Toluene at 110 °C, but a different ratio between the two derivatives is observed.(Scheme 3).These findings suggested the possibility of directing the selectivity of the process through careful tuning of the reaction conditions.Consequently, we decided to explore the reactivity of the 2-phenylethynyl aniline 1a using Brønsted acids as promoters under a variety of reaction conditions.During this study, side-reactions leading to the 2-aminoarylketone 6a, derived by the hydration of the C-C triple bond of 1a, and to the highly dense quinoline 7a, derived by its regioselective dimerization, were also observed.Yet, two control experiments highlighted that p-TsOH•H 2 O promotes the formation of 6a and 7a in both EtOH at 80 • C and Toluene at 110 • C, but a different ratio between the two derivatives is observed.(Scheme 3).These findings suggested the possibility of directing the selectivity of the process through careful tuning of the reaction conditions.Consequently, we decided to explore the reactivity of the 2-phenylethynyl aniline 1a using Brønsted acids as promoters under a variety of reaction conditions.The results of our investigation are summarised in Table 1.As shown, reaction parameters such as the temperature, reaction medium, nature of the Brønsted acid, and its loading have a significant effect on directing the regio-and chemoselectivity of the reaction.Performing the reaction in EtOH at 110 • C with a stoichiometric amount of p-TsOH•H 2 O favoured the prevalent regioselective dimerization of 1a over its hydration, leading to 2-(2-aminophenyl)quinoline 7a with a good yield of 70% (7a/8a = 80/20) (entry 1).Surprisingly, reducing the loading of p-TsOH•H 2 O resulted in a significant decrease in chemoselectivity, and 1-(2-aminophenyl)-2-phenylethan-1-one 6a was isolated with a 46% yield nearly comparable to 7a (entry 2).The use of methanesulfonic acid (MsOH) as a promoter afforded a mixture of 7a and the regioisomeric 3-(2-aminophenyl)quinoline 8a in an overall yield of 53% (Table 1, entry 3).Instead, the reaction mediated by trifluoromethanesulfonic acid (TfOH) yielded 2-phenylindole 5a along with the dimerization products 7a/8a (entry 4).Additionally, in this case, a partial inversion of regioselectivity was observed, with 8a predominating over 7a (entry 4 vs. entries 1 and 3).Similar regioselectivity, with a slight increase in the overall yield of 7a/8a, was observed when EtOH was replaced with Toluene as the reaction medium (entry 5).By contrast, the change of solvent was critical in the case of the p-TsOH•H 2 O acid-mediated reactions, where the use of i-PrOH instead of EtOH led to a drastic decrease in chemo-and regioselectivity (entry 6).Intriguingly, p-TsOH•H 2 O acid caused a puzzling change in reactivity when switching from the polar protic solvent to the halogenated solvent DCE.In fact, albeit in a moderate 54% yield, the 2-phenylindole 5a (along with 34% of recovered starting material 1a) was isolated as the sole product when performing the reaction at 40 • C in the presence of 0.2 equiv. of the p-TsOH .H 2 O (entry 7).Conversely, under identical temperature and solvent conditions, a stoichiometric amount of p-TsOH•H 2 O selectively led to hydration product 6a (entry 8).In the presence of 0.2 equiv. of p-TsOH .H 2 O, the formation of dimer 8a increased steadily as the temperature increased (entries 9-10).Yet, in DCE at 110 • C, a stoichiometric amount of p-TsOH .H 2 O promoted the formation of 8a in an appreciable 48% yield, along with a smaller amount of the regioisomeric quinoline 7a, which was obtained to a lower extent (19%) (entry 11).
While in THF, poor reactivity was observed as it resulted in the recovery of 56% of the starting material and a 15% yield of 6a (entry 12).Interesting results were achieved by performing the reaction in DMF.In this latter solvent, the dimerization of 1a was completely suppressed; however, in addition to 5a (45%) and 6a (22%), the formation of 3-phenylquinolin-4 (1H)-one 9a was observed to a significant extent (30%).This result suggested that, under these conditions, DMF can act as a C1 synthon [21].The 2-amino phenyl ketones 6 were reported to afford the phenylquinolin-4 (1H)-one 9 by means of sequential iron (III)-catalysed oxidation of alcohol/methyl arene, followed by condensation with amine/Mannich-type cyclisation/oxidation to complete the 4-quinolone ring [22].
Finally, in an attempt to improve the chemoselectivity of the reaction and rationalise the formation of 9a, we also attempted the reaction in DCE/Dimetoxymethane (DMM) [23,24].However, under the condition reported in entry 14, instead of 9a, the selective formation of the bis-indole 10a occurred with a satisfactory 76% yield (entry 14) [25].
To shed light on the diverse reaction pathways, quantum chemical calculations were performed in the framework of Density Functional Theory using the wB97XD functional, making use of a version of Grimme's D2 dispersion model [26] in conjunction with the 6-31G* basis set.[27] Notably, test calculations performed on some of the critical points (see below) using a larger basis set (6-311 + G*) showed similar results.All the critical points were located and characterised as true minima or first-order saddle points (hereafter Transition Structures, TS) through the calculations of the molecular vibrations in harmonic approximation.The eigenvectors with negative eigenvalues, obtained from the diagonalisation of the mass-weighted Hessian matrix, were also used to prove the actual role of each TS along the reaction route.The bulk effect of the solvent, either ethanol (EtOH) or 1,2-dichloroethane (DCE), was included in calculations using the mean-field approximation through the Polarisable Continuum Model [28] as implemented in the Gaussian16 software C.01. [29].Only in the case of EtOH (see below), the effect of one explicit solvent molecule was taken into account.The standard molar free energy was calculated for each species using standard statistical mechanical relations based on harmonic frequencies, moments of inertia, and excess free energies as obtained from DFT calculations.The reference state was established at 1.0 mol per litre for all species, except for the solvent, where its experimental density under specific experimental conditions was utilized.For rationalising the energy differences that emerged in the different reaction routes, additional calculations were performed at the same level of theory on some of the key transition structures and reaction intermediates using the Non-Covalent Interaction Index (NCI) analysis based on promolecular density [30] and RESP atomic charges [31].Both of these analyses were performed with the Multwfn program [32].
The optimised geometries and harmonic frequencies of all species are provided in the Supplementary Information.
We began the study by identifying the preferred protonation site in 1a and assessing the relative stability of the N-protonated species (Ia) and the two C-protonated species (IIa and IIIa) depicted in Figure 1 [33].As expected, calculations indicated that the N-protonated species Ia is, by far, the most abundant protomer, with a relative population exceeding 98% at 110 °C in both solvents at equilibrium.In fact, compared to IIa, the free energy of the anilinium ion Ia is lower by −14 kJ/mol (in DCE) and −17 kJ/mol (in EtOH) and lower by −78 kJ/mol (in DCE) and −84 kJ/mol (in EtOH) when compared to IIIa.Notably, these findings effectively explain the observed formation of the (insoluble) anilinium salt Ia when a stoichiometric amount of Brønsted acid is used.
To rationalise the distribution of the products under the various conditions of Table 1, we proceeded by calculating the energy profiles for the 1a dimerization reaction in DCE and EtOH (Figure 2).When the reaction is performed in DCE, the addition of 1a to Ia can originate the regioisomeric intermediates IVa (Figure 2, α'-attack, black lines) and Va (Figure 2, α-attack, black lines), with the latter species being largely preferred from a kinetic point of view with a ∆∆G # of 17 kJmol.Va should be likely responsible for the As expected, calculations indicated that the N-protonated species Ia is, by far, the most abundant protomer, with a relative population exceeding 98% at 110 • C in both solvents at equilibrium.In fact, compared to IIa, the free energy of the anilinium ion Ia is lower by −14 kJ/mol (in DCE) and −17 kJ/mol (in EtOH) and lower by −78 kJ/mol (in DCE) and −84 kJ/mol (in EtOH) when compared to IIIa.Notably, these findings effectively explain the observed formation of the (insoluble) anilinium salt Ia when a stoichiometric amount of Brønsted acid is used.
To rationalise the distribution of the products under the various conditions of Table 1, we proceeded by calculating the energy profiles for the 1a dimerization reaction in DCE and EtOH (Figure 2).When the reaction is performed in DCE, the addition of 1a to Ia can originate the regioisomeric intermediates IVa (Figure 2, α'-attack, black lines) and Va (Figure 2, α-attack, black lines), with the latter species being largely preferred from a kinetic point of view with a ∆∆G # of 17 kJmol.Va should be likely responsible for the formation of the regioisomer 8a isolated as the major product under the conditions of Table  Moreover, a further control experiment conducted by using p-toluidine as a proton scavenger confirmed the need for the presence of both 1a and anilinium salt Ia to eventually achieve the dimer 7a under the Brønsted acid-promoted reaction in EtOH at 110 °C (Scheme 5).
On the other hand, from a theoretical point of view, other scenarios become possible in EtOH.In fact, as shown in Figure 3, in this solvent, another quite irreversible addition of an alcohol molecule could take place through a reaction with a very negative ΔG°, yielding the two enol ethers VIa and VIIa (with the H and OEt groups in nearly degenerate syn or anti positions; see Supplementary Material for details) (Figure 3A).
Although the formation of IVa and Va from these intermediates is still conceivable, albeit with very high barriers (respectively 250 kJ/mol for IVa and 292 kJ/mol for Va (Figure 3B   By computing the reaction in EtOH as a solvent, the formation of Va remains kinetically favourable, albeit with a lower ∆∆G # of 9 kJmol (Figure 2, red lines).Therefore, the selective formation of regioisomer 7a under the conditions described in Table 1, entry 1, appears to be justified only if these conditions favour thermodynamic control of the reaction.
It has to be noted that a potential alternative reaction pathway to 7a through the condensation of 1a with 6a to give IVa was ruled out by the control experiment illustrated in Scheme 4 [34].In fact, the ketone 6a, intentionally added to the reaction mixture at the beginning, was quantitatively recovered at the end of the reaction.
Moreover, a further control experiment conducted by using p-toluidine as a proton scavenger confirmed the need for the presence of both 1a and anilinium salt Ia to eventually achieve the dimer 7a under the Brønsted acid-promoted reaction in EtOH at 110 • C (Scheme 5).
On the other hand, from a theoretical point of view, other scenarios become possible in EtOH.In fact, as shown in Figure 3, in this solvent, another quite irreversible addition of an alcohol molecule could take place through a reaction with a very negative ∆G • , yielding the two enol ethers VIa and VIIa (with the H and OEt groups in nearly degenerate syn or anti positions; see Supplementary Material for details) (Figure 3A).
1, appears to be justified only if these conditions favour thermodynamic control of the reaction.
It has to be noted that a potential alternative reaction pathway to 7a through the condensation of 1a with 6a to give IVa was ruled out by the control experiment illustrated in Scheme 4 [34].In fact, the ketone 6a, intentionally added to the reaction mixture at the beginning, was quantitatively recovered at the end of the reaction.Moreover, a further control experiment conducted by using p-toluidine as a proton scavenger confirmed the need for the presence of both 1a and anilinium salt Ia to eventually achieve the dimer 7a under the Brønsted acid-promoted reaction in EtOH at 110 °C (Scheme 5).
On the other hand, from a theoretical point of view, other scenarios become possible in EtOH.In fact, as shown in Figure 3, in this solvent, another quite irreversible addition of an alcohol molecule could take place through a reaction with a very negative ΔG°, yielding the two enol ethers VIa and VIIa (with the H and OEt groups in nearly degenerate syn or anti positions; see Supplementary Material for details) (Figure 3A).
Although the formation of IVa and Va from these intermediates is still conceivable, albeit with very high barriers (respectively 250 kJ/mol for IVa and 292 kJ/mol for Va (Figure 3B red lines), reactive channels with significantly lower energy profiles through the TS-C and TS-C' have been identified starting from VIa and VIIa (Figure 3B blue lines).The proximity of the ammonium and OEt groups in these intermediates allows the proton to transfer, facilitating the subsequent formation of the enol by the nucleophilic attack of a second EtOH molecule.Analogous pathways towards the hydration products could be found for the reaction in DCE at 40 °C (Figure 3C).While these findings help to rationalise   the acid-catalysed hydration of the triple bond (Table 1, entries 1-2 and 8), conversely to the Au-catalysed one [35], the origin of the high regioselectivity of the hydration reaction (only the ketone 6a is observed experimentally in both EtOH and DCE) remains to be clarified.As indicated below (Figure 4, left side), DFT calculations also provided the possible mechanism producing the indole 5a, which was obtained with the maximum yields of 54% under the conditions reported in Table 1, entry 7. Based on calculations, the formation of 5a is expected by a concerted pathway involving the proton transfer from p-TsOH to 1a with sinchronous cyclisation, through TS-D.The formation of the indole 5a could also account for the attainment of the bis-indole 10a by oxidative coupling when performing the reaction under the condition reported in Table 1, entry 14, where the in situ-generated formaldehyde could act as an oxidant [36].On the other hand, DFT calculations suggest the intermediate VIIIa as an alternative possible precursor of the bis-indole 10a.The relative energy profile leading to VIIIa is indicated in Figure 4, right side.Although the formation of IVa and Va from these intermediates is still conceivable, albeit with very high barriers (respectively 250 kJ/mol for IVa and 292 kJ/mol for Va (Figure 3B red lines), reactive channels with significantly lower energy profiles through the TS-C and TS-C' have been identified starting from VIa and VIIa (Figure 3B blue lines).The proximity of the ammonium and OEt groups in these intermediates allows the proton to transfer, facilitating the subsequent formation of the enol by the nucleophilic attack of a second EtOH molecule.Analogous pathways towards the hydration products could be found for the reaction in DCE at 40 • C (Figure 3C).While these findings help to rationalise the acid-catalysed hydration of the triple bond (Table 1, entries 1-2 and 8), conversely to the Au-catalysed one [35], the origin of the high regioselectivity of the hydration reaction (only the ketone 6a is observed experimentally in both EtOH and DCE) remains to be clarified.

VIa
As indicated below (Figure 4, left side), DFT calculations also provided the possible mechanism producing the indole 5a, which was obtained with the maximum yields of 54% under the conditions reported in Table 1, entry 7. Based on calculations, the formation of 5a is expected by a concerted pathway involving the proton transfer from p-TsOH to 1a with sinchronous cyclisation, through TS-D.The formation of the indole 5a could also account for the attainment of the bis-indole 10a by oxidative coupling when performing the reaction under the condition reported in Table 1, entry 14, where the in situ-generated formaldehyde could act as an oxidant [36].On the other hand, DFT calculations suggest the intermediate VIIIa as an alternative possible precursor of the bis-indole 10a.The relative energy profile leading to VIIIa is indicated in Figure 4, right side.As indicated below (Figure 4, left side), DFT calculations also provided the possible mechanism producing the indole 5a, which was obtained with the maximum yields of 54% under the conditions reported in Table 1, entry 7. Based on calculations, the formation of 5a is expected by a concerted pathway involving the proton transfer from p-TsOH to 1a with sinchronous cyclisation, through TS-D.The formation of the indole 5a could also account for the attainment of the bis-indole 10a by oxidative coupling when performing the reaction under the condition reported in Table 1, entry 14, where the in situ-generated formaldehyde could act as an oxidant [36].On the other hand, DFT calculations suggest the intermediate VIIIa as an alternative possible precursor of the bis-indole 10a.The relative energy profile leading to VIIIa is indicated in Figure 4, right side.This Brønsted acid-catalysed domino cycloisomerization/coupling/oxidation to furnish pharmaceutically relevant 3,3'-biindolyl products may represent an alternative to the heterogeneous cycloisomerization of 2-alkynylanilines to indoles catalysed by carbonsupported gold nanoparticles and subsequent homocoupling to 3,3'-biindoles [25].Substratecontrolled regioselective synthesis of 3,3 ′ -bisindole derivatives has been also established by the p-TsOH .H 2 O catalysed reaction of 2-indolylmethanols with indoles of CHCl 3 [37].
To test the generality of the procedure leading to the quinolines 7, selected 2-arylalkyny lanilines 1b-e were reacted under the optimized conditions reported in Table 1, entry 1.As indicated in Scheme 6, expected 2-(2-aminophenyl)quinolines 7b-d were predominantly obtained in satisfactory yields under aerobic conditions.The analogous regioselective outcome was reported in the Brønsted acid-promoted sequential hydration/condensation/double cyclization of pyridine-substituted 2-alkynylanilines [38].Only the 2-arylalkynylaniline 1e bearing the strong withdrawing p-CF 3 substituent in the aniline moiety gave in our cases as a main product the carbonyl derivative 5e [39].It is worth noting that the dimerization of 2-alkynylanilines into the corresponding 2-(2-aminophenyl)quinoline derivatives 7 was previously reported to occur only under anaerobic conditions via a Bi (OTf) 3 /MesCOOHcatalysed process, with the outcome being highly dependent on the solvent used.In fact, in such a procedure, hexafluoroisopropanol was found to be a crucial solvent and promoter for the success of the reaction [40].
However, in our procedure, the divergent hydration reaction also prevailed by performing the reaction on the alkyl and the trimethylsilyl-substituted alkynylanilines (Scheme 7).Conversely, the 2-phenyl-4-methyl-2-(2-aminophenyl)quinoline 7g,h was isolated in high yield through the Bi(OTf) 3 /MesCOOH-catalysed or InBr 3 promoted processes of 2-ethynylanilines 1g,h [41].Moreover, gold(III)/silver (I)-based catalysts [42], heterobimetallic catalysts of the type CpRu(PPh 3 )Cl(µ-dppm)AuI [43], and dinuclear gold catalytic systems [44] with no silver co-catalysts allowed the dimerization of a broad range of 2-ethynylaniline substrates under mild conditions.Interestingly, as shown in Scheme 7, Equations ( 2) and (3), by carrying out the reaction on the substrates 1g,h, the side-products 7-azabicyclo[4.2.0]octa-1(6),2,4-trien-8-ol derivatives 11g,h were isolated as a consequence of the intramolecular aminocyclization.Their formation, albeit in a low yield, seems to be promising for further research towards the synthesis of challenging 4-membered cyclic hemiaminals 11. entry 1.As indicated in Scheme 6, expected 2-(2-aminophenyl)quinolines 7b-d were predominantly obtained in satisfactory yields under aerobic conditions.The analogous regioselective outcome was reported in the Brønsted acid-promoted sequential hydration/condensation/double cyclization of pyridine-substituted 2-alkynylanilines [38].Only the 2-arylalkynylaniline 1e bearing the strong withdrawing p-CF3 substituent in the aniline moiety gave in our cases as a main product the carbonyl derivative 5e [39].It is worth noting that the dimerization of 2-alkynylanilines into the corresponding 2-(2aminophenyl)quinoline derivatives 7 was previously reported to occur only under anaerobic conditions via a Bi (OTf)3/MesCOOH-catalysed process, with the outcome being highly dependent on the solvent used.In fact, in such a procedure, hexafluoroisopropanol was found to be a crucial solvent and promoter for the success of the reaction [40].However, in our procedure, the divergent hydration reaction also prevailed by performing the reaction on the alkyl and the trimethylsilyl-substituted alkynylanilines (Scheme 7).Conversely, the 2-phenyl-4-methyl-2-(2-aminophenyl)quinoline 7g,h was isolated in high yield through the Bi(OTf)3/MesCOOH-catalysed or InBr3 promoted processes of 2-ethynylanilines 1g,h [41].Moreover, gold(III)/silver (I)-based catalysts [42], heterobimetallic catalysts of the type CpRu(PPh3)Cl(µ-dppm)AuI [43], and dinuclear gold catalytic systems [44] with no silver co-catalysts allowed the dimerization of a broad range of 2-ethynylaniline substrates under mild conditions.Interestingly, as shown in Scheme 7, Equations ( 2) and (3), by carrying out the reaction on the substrates 1g,h, the sideproducts 7-azabicyclo[4.2.0]octa-1(6),2,4-trien-8-ol derivatives 11g,h were isolated as a consequence of the intramolecular aminocyclization.Their formation, albeit in a low yield, seems to be promising for further research towards the synthesis of challenging 4membered cyclic hemiaminals 11.Finally, according to the data reported in Table 1, we proceeded with the synthesis of representative regioisomeric structures 8 by switching to DCE as the solvent (Scheme 8).Nicely, in DCE at 110 °C, the use of 1 equivalent of p-TsOH acid resulted in reverse regioselectivity, yielding quinoline derivatives 8c and 8d in satisfactory 55% and 64% yields, respectively (Scheme 8, Equations ( 1) and ( 2)).These results are in line with those observed with the Rh (III)-catalysed dimerization under anaerobic conditions in hexafluoroisopropanol [45].Notably, as demonstrated in Scheme 8, Equation (3), in our procedure, the amount of p-TsOH•H2O resulted in being essential to controlling the regioisomeric outcome.Finally, according to the data reported in Table 1, we proceeded with the synthesis of representative regioisomeric structures 8 by switching to DCE as the solvent (Scheme 8).Nicely, in DCE at 110 • C, the use of 1 equivalent of p-TsOH acid resulted in reverse regioselectivity, yielding quinoline derivatives 8c and 8d in satisfactory 55% and 64% yields, respectively (Scheme 8, Equations ( 1) and ( 2)).These results are in line with those observed with the Rh (III)-catalysed dimerization under anaerobic conditions in hexafluoroisopropanol [45].Notably, as demonstrated in Scheme 8, Equation (3), in our procedure, the amount of p-TsOH•H 2 O resulted in being essential to controlling the regioisomeric outcome.

Chemistry-General Part
Flash chromatography was carried out using silica gel 60 (70-230 mesh, Merck, Darmstadt, Germany).Yields are given for isolated products showing one spot on a TLC plate, and no impurities were detectable in the NMR spectrum. 1H NMR spectra were recorded at 400.13 MHz on a Bruker Avance III spectrometer using the standard Bruker "zg30" sequence.Chemical shifts (in ppm) were referenced to TMS (δ = 0.00 ppm), CDCl 3 (δ = 7.26 ppm), or DMSO (δ = 2.49 ppm) as an internal standard. 13C NMR spectra were taken on the same machine at 100.613 MHz, using the standard Bruker "zgpg30" proton-decupled sequence.Carbon spectra were calibrated with TMS (δ = 0.0 ppm) or CDCl 3 (δ = 77.0ppm) as an internal standard. 19F-NMR spectra were taken on the same machine at 376.498 MHz using the standard Bruker "zgcigqn" proton-decupled sequence and calibrated with trifluoroacetic acid (δ = −76.55ppm) with the substitution method.Coupling constants (J) are quoted in Hertz.Mass measurements were performed using a MALDI-TOF spectrometer AB SCIEX TOF/TOF 5800 (SCIEX, Framingham, MA, USA) using a matrix in combination with KI for the ionisation.
Preparation of the 2-(p-Tolylethynyl)aniline (1b) [46].A 50-mL round-bottomed flask containing a magnetic stir bar was charged with 2-iodoaniline (2.240 g, 10.2 mmol, 1.0 equiv), 7.1 mL of Et 3 N, and 3 mL of DMF.The resulting reaction mixture was then added with Pd (PPh 3 ) 4 (294.5 mg, 0.255 mmol, 0.025 equiv) and CuI (96.9 mg, 0.510 mmol, 0.050 equiv).The heterogeneous mixture was degassed by passing through a steady stream of nitrogen before the addition of ethynyltrimethylsilane (2.20 mL, 1.500 g, 15.300 mmol, 1.5 equiv) via a syringe.The reaction mixture was allowed to stir at room temperature under nitrogen overnight (18-20 h).Upon completion, the mixture was diluted by the addition of aqueous HCl (0.1 M).The mixture was extracted with EtOAc, and the combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the crude material.The crude product was taken up in 10 mL of MeOH, followed by the addition of K 2 CO 3 (282.0mg, 2.040 mmol, 0.2 equiv).The resulting mixture was stirred at room temperature for 2 h.Then, the reaction mixture was diluted with aqueous HCl (0.1 M) and extracted with CHCl 3 .The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography eluting hexane/EtOAc 99/1 to provide 2-ethynylaniline (734.0 mg, 62% over 2 steps).

Conclusions
In summary, we have explored the key factors that influence product selectivity in Brønsted acid-catalysed/mediated reactions of 2-alkynylanilines.The methodologies presented here provide viable alternatives to metal-catalysis approaches, often offering complementary selectivity through simple adjustments such as changing the solvent, varying the amount of the Brønsted acid promoter, and/or modifying the reaction temperature.Using essentially the same catalytic system, we established optimal conditions for selectively producing dimerization products 7 or 8, directing the reaction towards hydration product 6, or achieving cycloisomerization to indoles 5 and bis-indoles 10.Mechanistic insights into the origins of chemo-and regioselectivity were obtained through quantum chemical calculations using Density Functional Theory.

Scheme 2 .
Scheme 2. Product selectivity control in the sequential reaction of 2-alkynylanilines 1 with ketones.

Scheme 2 .
Scheme 2. Product selectivity control in the sequential reaction of 2-alkynylanilines 1 with ketones.

Scheme 2 .
Scheme 2. Product selectivity control in the sequential reaction of 2-alkynylanilines 1 with ketones.

Figure 1 .
Figure 1.Protonation site distribution and relative free-energies of Ia, IIa, and IIIa in DCE and EtOH.

Figure 1 .
Figure 1.Protonation site distribution and relative free-energies of Ia, IIa, and IIIa in DCE and EtOH.

Figure 2 .
Figure 2. (A) Reaction scheme for 1a dimerization under acid conditions and relative free energies in kJ/mol at 110 °C in DCE (black lines) and EtOH (red lines).(B) Possible reaction pathways for the formation of 8a and (C) 7a.
red lines), reactive channels with significantly lower energy profiles through the TS-C and TS-C' have been identified starting from VIa and VIIa (Figure 3B blue lines).The proximity of the ammonium and OEt groups in these intermediates allows the proton to transfer, facilitating the subsequent formation of the enol by the nucleophilic attack of a second EtOH molecule.Analogous pathways towards the hydration products could be

Figure 2 .
Figure 2. (A) Reaction scheme for 1a dimerization under acid conditions and relative free energies in kJ/mol at 110 • C in DCE (black lines) and EtOH (red lines).(B) Possible reaction pathways for the formation of 8a and (C) 7a.

Figure 2 .
Figure 2. (A) Reaction scheme for 1a dimerization under acid conditions and relative free energies in kJ/mol at 110 °C in DCE (black lines) and EtOH (red lines).(B) Possible reaction pathways for the formation of 8a and (C) 7a.

Table 1 .
Screening of the reaction conditions.
a Reactions have been carried out on a 0.37-0.78mmol scale.b Yields refer to isolated products.

Table
Control experiment ruling out the formation of 7a from 6a (Reaction conditions: Table1, entry 1).